Loss of expression of miR-335 is implicated in hepatic stellate cell migration and activation. Exp Cell Res

Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, No.415 Fengyang Road, Shanghai 200003, China.
Experimental Cell Research (Impact Factor: 3.25). 07/2011; 317(12):1714-25. DOI: 10.1016/j.yexcr.2011.05.001
Source: PubMed


Activation and migration of resident stellate cells (HSCs) within the hepatic space of Disse play an important role in hepatic fibrosis, which accounts for the increased numbers of activated HSCs in areas of inflammation during hepatic fibrosis. Currently, microRNAs have been found to play essential roles in HSC differentiation, proliferation, apoptosis, fat accumulation and collagen production. However, little is known about microRNA mediated HSC activation and migration. In this study, the miRNA expression profiles of quiescent HSCs, partially activated HSCs and fully activated HSCs were compared in pairs. Gene ontology (GO) and GO-Map network analysis indicated that the activation of HSCs was regulated by microRNAs. Among them miR-335 was confirmed to be significantly reduced during HSC activation by qRT-PCR, and restoring expression of miR-335 inhibited HSC migration and reduced α-SMA and collagen type I. Previous study revealed that tenascin-C (TNC), an extracellular matrix glycoprotein involved in cell migration, might be a target of miR-335. Therefore, we further studied the TNC expression in miR-335 over-expressed HSCs. Our data showed that exogenous TNC could enhance HSC migration in vitro and miR-335 restoration resulted in a significant inhibition of TNC expression. These results demonstrated that miR-335 restoration inhibited HSC migration, at least in part, via downregulating the TNC expression.

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    • "While MEST has been reported to enhance the capacity for lipid storage in adipocytes [43], miR-335 is upregulated in the liver and adipose tissue of diabetic db/db mice and promotes lipid accumulation during adipocyte differentiation in the murine 3T3-L1 cell model [41]. It has also been linked with adipose tissue inflammation [44] and more recently shown to inhibit hepatic stellate cell activation and migration, suggesting a potentially positive role in reducing hepatic fibrosis [45]. Given that liver fibrosis and increased TG (both in liver and in circulation) are characteristics of NAFLD, miR-335 presents a potentially valuable therapeutic candidate for the diagnosis and treatment of NAFLD. "
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    • "MicroRNAs (miRNAs) are endogenous, small and noncoding RNAs, which have the ability to regulate gene expression in a mature form by binding to the 3′-untranslated region (3′-UTR) of target mRNAs and repressing translation or inducing mRNA cleavage [6,7]. Previous studies have revealed that miRNAs play indispensable roles in the progress of liver fibrosis by being involved in the differentiation, fat metabolism and ECM production of HSCs [8,9] and the proliferation and apoptosis of HSCs [10-12]. Over-expression of miR-146a can suppress TGF-β1-induced HSC proliferation and induce HSC apoptosis [11]. "
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    ABSTRACT: In the process of hepatic fibrosis, hepatic stellate cells (HSCs) can be activated by many inflammatory cytokines. The transforming growth factor-beta1 (TGF-beta1) is one of the main profibrogenic mediators. Recently, some studies have also shown that microRNAs (miRNAs) play essential roles in the progress of liver fibrosis by being involved in the differentiation, fat metabolism and ECM production of HSCs. The expression of miR-454 in LX-2 cells treated with TGF-beta1 and in the fibrotic livers with Schistosoma japonicum infection was detected by qRT-PCR. The role of miR-454 on LX-2 cells was then analyzed by Western blot, flow cytometry and luciferase assay. The results showed that the expression of miR-454 was down-regulated in the TGF-beta1-treated LX-2 cells and miR-454 could inhibit the activation of HSCs by directly targeting Smad4. However, we found that miR-454 had no effect on cell cycle and cell proliferation in TGF-beta1-treated LX-2. Besides these, miR-454 was found to be regulated in the process of Schistosoma japonicum infection. All the results suggested that miR-454 could provide a novel therapeutic approach for treating liver fibrosis, especially the liver fibrosis induced by Schistosoma japonicum.
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    • "Indeed, Dickkopf-related protein 1 (DKK1) and breast cancer 1, early onset (BRCA1) are known targets of miR-335 (Heyn et al. 2011; Zhang et al. 2011). Because a recent study has suggested that miR-335 regulates cell migration (Chen et al. 2011), which, in turn, is regulated by actin (Rottner and Stradal 2011), we evaluated regulation of the cytoskeleton by miR-335-5p in the present study. "
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